DESCRIPTION (Applicants Description) A P01 on the genetic epidemiology of breast cancer is proposed. It builds upon a unique resource of 426 four-to five-generation families ascertained through breast cancer patients originally ascertained between 1940 and 1952. Important observations have enriched this resource during 5 years of funding from an R01. The theme of this project is the interaction of genes and environment in the pathogenesis of this disease. These multi generation families offer distinct advantages in efforts to investigate this important subject. Project 1 seeks to I) determine the frequency of genetic alterations in BRCA1 and BRCA2 in a population-based sample of 260 families with at least two cases of breast or ovarian cancer and, II) to explore geno-environment risk interactions. Project 2 is designed to test the hypothesis that Bioactivation of estrogens, under the control of polymorphic genes, can lead to direct genotoxicity of DNA and increased risk of breast cancer. Project 3 is a genetic linkage study to identify the chromosomal location of a gene that is associated with increased mammographic breast density, a major risk factor for breast cancer. Project 4 is a follow up study of this powerful cohort of families. It seeks to investigate the natural history of mammographic breast density, and will examine important new risk factor data on adolescent diet and early life exposures. In addition, this follow-up survey will ascertain additional breast cancer cases for Projects 1 and 2. The projects are supported by four cores that are essential to carry out the overall P01: administration, biostatistics, mammography, and epidemiology. The investigative team is multidisciplinary, experienced, and brings a history of productive collaborations. The findings from this important project could be critical to our understanding of the genetic epidemiology of breast cancer.